This project seeks to understand the physiology and pathophysiology of ovarian follicle development and function, and to thereby develop clinical diagnostic and therapeutic applications for women with ovulatory disorders. During this period we have focused on premature ovarian failure, a condition which prematurely terminates fertility in 1% of women. We have particular interest in autoimmune-mediated ovarian failure and seek to improve our understanding of this condition through clinical research and through basic immunologic research employing a mouse model in which autoimmune ovarian failure is induced by neonatal thymectomy. During this period our research has demonstrated that patients with premature ovarian failure as a group have increased T lymphocyte activation as determined by flow cytometry, and that a less complex method to detect immune activation, enzyme linked immunosorbent assay measurement of soluble interleukin 2 receptors, is unable to detect this activation. Our research in mice has demonstrated that neonatal thymectomy induces a failure of deletion of certain self-reactive lymphocytes which are normally deleted from the T lymphocyte repertoire, but that despite the presence of these self-reactive T lymphocytes, tolerance is nevertheless maintained by secondary mechanisms. In the coming years we plan to evaluate treatments for premature ovarian failure by controlled prospective trials and to assess the pathophysiologic role of immunoglobulins and T lymphocytes in autoimmune premature ovarian failure. We also plan to define the pathogenesis of autoimmune ovarian failure in the neonatally thymectomized mouse by using immunohistochemical techniques to characterize the initial events in this process, and by using cell culture techniques to assess T lymphocyte proliferation in response to ovarian antigens.